This invention relates generally to chemical entities, particularly steroidal C-17 benzoazoles, pyrimidinoazoles (azabenzoazoles) and diazines and, more particularly, to prodrugs of these entities. The invention also includes methods for the synthesis of the prodrugs of the steroidal C-17 benzoazoles, pyrimidinoazoles and diazines, and the use of the prodrugs in treating diseases and conditions such as cancer.
Prostate cancer (PCA) is the most common malignancy and age-related cause of cancer death worldwide. Apart from lung cancer, PCA is the most common form of cancer in men and the second leading cause of death in American men. In the United States in 2008, an estimated 186,320 new case of prostate cancer will be diagnosed and about 28,660 men will die of this disease, with African American men and Jamaican men of African decent having the highest incidence rates in the world1. Androgens play an important role in the development, growth, and progression of PCA2. The two most important androgens in this regard are testosterone (T) and dihydrotestosterone (DHT). The testes synthesize about 90% of T and the rest (10%) is synthesized by the adrenal glands. T is further converted to the more potent androgen DHT by the enzyme steroid 5α-reductase that is localized primarily in the prostate3. Huggins et al. introduced androgen deprivation as therapy for advanced and metastatic PCA in 19414. Thereafter, androgen ablation therapy has been shown to produce the most beneficial responses in multiple settings in PCA patients5. Orchidectomy (either surgical or medical with a GnRH agonist) remains the standard treatment option for most prostate cancer patients. Medical and surgical orchidectomy reduces or eliminates androgen production by the testes but does not affect androgen synthesis in the adrenal glands. Several studies have reported that a combination therapy of orchidectomy with antiandrogens, to inhibit the action of adrenal androgens, significantly prolongs the survival of PCA patients6-8. In a recent featured article by Mohler and colleagues,9 it was clearly demonstrated that T and DHT occur in recurrent PCA tissues at levels sufficient to activate androgen receptor. In addition, using microarray-based profiling of isogenic PCA xenograft models, Sawyers and colleagues10 found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. Potent and specific compounds that inhibit androgen synthesis in the testes, adrenals, and other tissue may be more effective for the treatment of PCA11.
In the testes and adrenal glands, the last step in the biosynthesis of T involves two key reactions, which act sequentially and they are both catalyzed by a single enzyme, the cytochrome P450 monooxygenase 17α-hydroxylase/17,20-lyase (CYP17)12. Ketoconazole, an antifungal agent, and by virtue of inhibiting P450 enzymes is also a modest CYP17 inhibitor, and has been used clinically for the treatment of PCA13. It is reported that careful scheduling of treatment can produce prolonged responses in otherwise hormone-refractory prostate cancer patients14. Furthermore, ketoconazole was found to retain activity in advanced PCA patients with progression despite flutamide withdrawal15. Although, ketoconazole has now been withdrawn from use because of liver toxicity and other side effects this suggests that more potent and selective inhibitors of CYP17 could provide useful agents for treating this disease, even in advanced stages and in some patients who may appear to be hormone refractory.
A variety of potent steroidal and non-steroidal inhibitors of CYP17 have been reported and some have been shown to be potent inhibitors of testosterone production in rodent models11. Recently, Jarman and colleagues have described the hormonal impact of their most potent CYP17 inhibitor, abiraterone in patients with prostate cancer16. Some of our potent CYP17 inhibitors have been shown to also inhibit 5α-reductase and/or are potent antiandrogens with potent antitumor activityl11,17. Further illustrative of the background of the invention are U.S. Pat. Nos. 5,994,335; 6,200,965; and, 6,444,683.